Abstract
Li–Fraumeni syndrome (LFS) is an autosomal-dominant cancer predisposition syndrome of which the majority is caused by TP53 germline mutations and is characterised by different tumour types occurring at relatively young age. Recently, it was shown that a single-nucleotide polymorphism (SNP) in the MDM2 gene, SNP309 (T>G variation), was associated with accelerated tumour formation in LFS patients who carry a TP53 germline mutation. To confirm this finding in different populations, we screened 25 Dutch and 11 Finnish TP53 mutation carriers for the presence of the SNP309 G allele in the MDM2 gene. Additionally, we investigated whether the SNP309 G allele plays a role in 72 Dutch TP53-negative LFS and LFS-related patients. In the TP53 germline mutation carriers, a significant difference was seen in the mean age of tumour onset for the SNP309 G allele group, that is, 29.7 years as compared to the SNP309 homozygous T group 45.5 years (P=0.005). In patients of LFS and LFS-related TP53-negative families, no difference was seen in the mean age of tumour onset. However, this TP53-negative group did show a significantly higher percentage of SNP309 homozygotes (G/G) compared to the general population (P=0.02). In conclusion, TP53 germline mutation carriers who have an SNP309 G allele have an earlier onset of tumour formation. The higher prevalence of MDM2 SNP309 homozygous G/G carriers in the TP53-negative group suggests that this allele contributes to cancer susceptibility in LFS and LFS-related families.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Li FP, Fraumeni Jr JF : Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 1969; 71: 747–752.
Li FP, Fraumeni Jr JF, Mulvihill JJ et al: A cancer family syndrome in twenty-four kindreds. Cancer Res 1988; 48: 5358–5362.
Birch JM, Hartley AL, Tricker KJ et al: Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li–Fraumeni families. Cancer Res 1994; 54: 1298–1304.
Eeles RA : Germline mutations in the TP53 gene. Cancer Surv 1995; 25: 101–124.
Malkin D, Li FP, Strong LC et al: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990; 250: 1233–1238.
Varley JM : Germline TP53 mutations and Li–Fraumeni syndrome. Hum Mutat 2003; 21: 313–320.
Bachinski LL, Olufemi SE, Zhou X et al: Genetic mapping of a third Li–Fraumeni syndrome predisposition locus to human chromosome 1q23. Cancer Res 2005; 65: 427–431.
Houlston RS, Peto J : The search for low-penetrance cancer susceptibility alleles. Oncogene 2004; 23: 6471–6476.
Bond GL, Hu W, Bond EE et al: A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 2004; 119: 591–602.
Bougeard G, Baert-Desurmont S, Tournier I et al: Impact of the MDM2 SNP309 and TP53 Arg72Pro polymorphism on age of tumour onset in Li–Fraumeni syndrome. J Med Genet 2005; 43: 531–533.
Wilkening S, Bermejo JL, Burwinkel B et al: The single nucleotide polymorphism IVS1+309 in mouse double minute 2 does not affect risk of familial breast cancer. Cancer Res 2006; 66: 646–648.
Acknowledgements
We thank Dr Carl Blomqvist and research nurse Nina Puolakka for their kind help. The work was supported by the Dutch National Genomic Initiative, Cancer Genomics Centre, the Helsinki University Central Hospital Research Fund, Academy of Finland (project 110663), Finnish Cancer Society and the Sigrid Juselius Foundation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ruijs, M., Schmidt, M., Nevanlinna, H. et al. The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li–Fraumeni syndrome and related phenotypes. Eur J Hum Genet 15, 110–114 (2007). https://doi.org/10.1038/sj.ejhg.5201715
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5201715
Keywords
This article is cited by
-
A common polymorphism in the retinoic acid pathway modifies adrenocortical carcinoma age-dependent incidence
British Journal of Cancer (2020)
-
Li–Fraumeni syndrome heterogeneity
Clinical and Translational Oncology (2020)
-
p53 signaling pathway polymorphisms, cancer risk and tumor phenotype in TP53 R337H mutation carriers
Familial Cancer (2018)
-
Evaluation of TP53 Pro72Arg and MDM2 SNP285–SNP309 polymorphisms in an Italian cohort of LFS suggestive patients lacking identifiable TP53 germline mutations
Familial Cancer (2016)
-
Impact of MDM2 gene polymorphism on sarcoma risk
Tumor Biology (2015)
